Nickel alterations of TLR2-dependent chemokine profiles in lung fibroblasts are mediated by COX-2

Am J Respir Cell Mol Biol. 2008 May;38(5):591-9. doi: 10.1165/rcmb.2007-0314OC. Epub 2007 Dec 20.


Particulate matter air pollution (PM) has been linked with chronic respiratory diseases. Real-life exposures are likely to involve a mixture of chemical and microbial stimuli, yet little attention has been paid to the potential interactions between PM components (e.g., Ni) and microbial agents on the development of inflammatory-like conditions in the lung. Using the Toll-like receptor (TLR)-2 agonist MALP-2 as a lipopeptide relevant to microbial colonization, we hypothesized that nickel sensitizes human lung fibroblasts (HLF) for microbial-driven chemokine release through modulation of TLR signaling pathways. NiSO(4) (200 muM) synergistically enhanced CXCL8, yet antagonized CXCL10 mRNA expression and protein release from HLF in response to MALP-2. RT(2)-PCR pathway-focused array results indicated that NiSO(4) exposure did not alter the expression of TLRs or their downstream signaling mediators, yet significantly increased the expression of cyclooxygenase 2 (COX-2). Moreover, when NiSO(4) was given in combination with MALP-2, there was an amplified induction of COX-2 mRNA and protein along with its metabolic product, PGE2, in HLF. The COX-2 inhibitor, NS-398, attenuated NiSO(4) and MALP-2-induced PGE2 and CXCL8 release and partially reversed the NiSO(4)-dependent inhibition of MALP-2-induced CXCL10 release from HLF. These data indicate that NiSO(4) alters the pattern of TLR-2-dependent chemokine release from HLF via a COX-2-mediated pathway. The quantitative and qualitative effects of NiSO(4) on microbial-driven chemokine release from HLF shed new light on how PM-derived metals can exacerbate respiratory diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cells, Cultured
  • Chemokine CXCL10 / metabolism
  • Chemokines / biosynthesis*
  • Chemokines / genetics
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 / physiology*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Profiling
  • Humans
  • Interleukin-8 / metabolism
  • Lipopeptides
  • Lung / cytology
  • Lung / drug effects
  • Lung / enzymology*
  • Lung / pathology
  • Nickel / adverse effects*
  • Oligopeptides / physiology
  • Toll-Like Receptor 2 / agonists
  • Toll-Like Receptor 2 / physiology*


  • CXCL10 protein, human
  • CXCL8 protein, human
  • Chemokine CXCL10
  • Chemokines
  • Cyclooxygenase 2 Inhibitors
  • Interleukin-8
  • Lipopeptides
  • Oligopeptides
  • TLR2 protein, human
  • Toll-Like Receptor 2
  • nickel sulfate
  • Nickel
  • macrophage stimulatory lipopeptide 2
  • Cyclooxygenase 2
  • PTGS2 protein, human